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An ultrapotent synthetic nanobody neutralizes SARS-CoV-2 by stabilizing inactive Spike.
- Schoof, Michael;
- Faust, Bryan;
- Saunders, Reuben A;
- Sangwan, Smriti;
- Rezelj, Veronica;
- Hoppe, Nick;
- Boone, Morgane;
- Billesbølle, Christian B;
- Puchades, Cristina;
- Azumaya, Caleigh M;
- Kratochvil, Huong T;
- Zimanyi, Marcell;
- Deshpande, Ishan;
- Liang, Jiahao;
- Dickinson, Sasha;
- Nguyen, Henry C;
- Chio, Cynthia M;
- Merz, Gregory E;
- Thompson, Michael C;
- Diwanji, Devan;
- Schaefer, Kaitlin;
- Anand, Aditya A;
- Dobzinski, Niv;
- Zha, Beth Shoshana;
- Simoneau, Camille R;
- Leon, Kristoffer;
- White, Kris M;
- Chio, Un Seng;
- Gupta, Meghna;
- Jin, Mingliang;
- Li, Fei;
- Liu, Yanxin;
- Zhang, Kaihua;
- Bulkley, David;
- Sun, Ming;
- Smith, Amber M;
- Rizo, Alexandrea N;
- Moss, Frank;
- Brilot, Axel F;
- Pourmal, Sergei;
- Trenker, Raphael;
- Pospiech, Thomas;
- Gupta, Sayan;
- Barsi-Rhyne, Benjamin;
- Belyy, Vladislav;
- Barile-Hill, Andrew W;
- Nock, Silke;
- Liu, Yuwei;
- Krogan, Nevan J;
- Ralston, Corie Y;
- Swaney, Danielle L;
- García-Sastre, Adolfo;
- Ott, Melanie;
- Vignuzzi, Marco;
- QCRG Structural Biology Consortium;
- Walter, Peter;
- Manglik, Aashish
- et al.
Published Web Location
https://doi.org/10.1126/science.abe3255Abstract
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus enters host cells via an interaction between its Spike protein and the host cell receptor angiotensin-converting enzyme 2 (ACE2). By screening a yeast surface-displayed library of synthetic nanobody sequences, we developed nanobodies that disrupt the interaction between Spike and ACE2. Cryo-electron microscopy (cryo-EM) revealed that one nanobody, Nb6, binds Spike in a fully inactive conformation with its receptor binding domains locked into their inaccessible down state, incapable of binding ACE2. Affinity maturation and structure-guided design of multivalency yielded a trivalent nanobody, mNb6-tri, with femtomolar affinity for Spike and picomolar neutralization of SARS-CoV-2 infection. mNb6-tri retains function after aerosolization, lyophilization, and heat treatment, which enables aerosol-mediated delivery of this potent neutralizer directly to the airway epithelia.
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